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  • 1
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. 9 ( 2014-09), p. 2620-2628
    Abstract: We aimed to develop a risk score (intracerebral hemorrhage–associated pneumonia score, ICH-APS) for predicting hospital-acquired stroke-associated pneumonia (SAP) after ICH. Methods— The ICH-APS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Variables routinely collected at presentation were used for predicting SAP after ICH. For testing the added value of hematoma volume measure, we separately developed 2 models with (ICH-APS-B) and without (ICH-APS-A) hematoma volume included. Multivariable logistic regression was performed to identify independent predictors. The area under the receiver operating characteristic curve (AUROC), Hosmer–Lemeshow goodness-of-fit test, and integrated discrimination index were used to assess model discrimination, calibration, and reclassification, respectively. Results— The SAP was 16.4% and 17.7% in the overall derivation (n=2998) and validation (n=2000) cohorts, respectively. A 23-point ICH-APS-A was developed based on a set of predictors and showed good discrimination in the overall derivation (AUROC, 0.75; 95% confidence interval, 0.72–0.77) and validation (AUROC, 0.76; 95% confidence interval, 0.71–0.79) cohorts. The ICH-APS-A was more sensitive for patients with length of stay 〉 48 hours (AUROC, 0.78; 95% confidence interval, 0.75–0.81) than those with length of stay 〈 48 hours (AUROC, 0.64; 95% confidence interval, 0.55–0.73). The ICH-APS-A was well calibrated (Hosmer–Lemeshow test) in the derivation ( P =0.20) and validation ( P =0.66) cohorts. Similarly, a 26-point ICH-APS-B was established. The ICH-APS-A and ICH-APS-B were not significantly different in discrimination and reclassification for SAP after ICH. Conclusion— The ICH-APSs are valid risk scores for predicting SAP after ICH, especially for patients with length of stay 〉 48 hours.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
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    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 2
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 1-1
    Abstract: Background: Ibrutinib, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for the treatment of relapsed/refractory (R/R) Mantle cell lymphoma (MCL). Both single-agent ibrutinib and combination of ibrutinib with rituximab have achieved great efficacy with manageable toxicity (Wang,NEJM2013; Wang,Lancet Oncol2015; Dreyling,Lancet2015). This study, for the first time, analyzed the real-world effectiveness and tolerability of ibrutinib for MCL patients in China. Methods: This multi-center, retrospective cohort study enrolled adult patients (pts) with pathologically confirmed MCL who initiated ibrutinib-containing treatment between November 2017 (date of commercialization) and April 2020. Eligible patients were retrospectively divided into 3 subgroups to receive ibrutinib-containing treatments for different purposes: R/R MCL group, newly diagnosed MCL group and maintenance therapy group. This analysis reports the baseline characteristics, efficacy and safety profiles in R/R MCL patients. Results: A total of 67 R/R MCL pts receiving ibrutinib-containing treatment from 9 medical centers in China were included in this analysis. At ibrutinib initiation, the median age was 61.0 (range 39-81) years, 68.7% were male and 81.8% had Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Approximately three-quarters of pts (72.3%) had 1 previous line of therapy before ibrutinib. Baseline characteristics are summarized in Table 1. Of all patients enrolled, 53.7% (36/67) of pts received ibrutinib monotherapy and 46.3% (31/67) received ibrutinib-containing combination therapy. IR (ibrutinib and rituximab) (16/31, 51.6%) and IR2 (ibrutinib, rituximab and lenalidomide) (5/31, 16.1%) were the two most common combination regimens. Nine patients (29.0%) received ibrutinib plus R-chemotherapy. Although no statistically significant difference was found in listed baseline characteristics between these two groups, a larger percentage of pts with bone marrow involvement (58.1% vs 35.7%) and bulky mass (largest diameter) ≥5 cm (46.4% vs 27.3%) were observed in combination therapy group. Best overall response rate (ORR) was 65.7% (20.9% complete remission [CR]). Median time to response (TTR) was 4.1 months and median duration of response (DOR) was 18.4 months. With a median follow-up of 10.2 months, median progression-free survival (PFS) was 21.3 months (95% confidence interval [CI] , 15.2 - not available [NA]) (Figure 1A). PFS rates were 86.0%, 69.8% and 47.6% at 6 months, 1 year and 2 years. With a median follow-up of 11.2 months, median overall survival (OS) was not reached with OS rates of 98.5%, 87.9% and 76.3% at 6 months, 1 year and 2 years (Figure 1B). Compared with ibrutinib monotherapy, combination therapy showed higher ORR (50.0% vs 83.9%), CR rate (8.3% vs 35.5%) and shorter TTR (median TTR, 6.0 vs 2.2 months; Logrank,p=0.0012) (Figure 2A). Although the combination therapy had a trend for better PFS, no statistically significant benefit in PFS or OS was observed (Figure 2B, C). Safety analysis focused on 55 R/R MCL pts from 3 centers with adequate adverse events information. The most common treatment emergent adverse events (TEAEs) of interest were infection (8/55, 14.6%), rash (8/55, 14.6%), bleeding (5/55, 9.1%; 1/5 was major bleeding [subdural hemorrhage]) and atrial fibrillation (3/55, 5.5%). Four pts (7.3%) experienced grade 3-4 TEAE (neutropenia, n=2; neutropenia and lung infection, n=1; subdural hemorrhage, n=1). Six pts (10.9%) had ≥1 temporary ibrutinib discontinuation due to TEAE (infection, n=3; neutropenia, n=1; rash, n=1; vomiting, n=1). One patient discontinued ibrutinib permanently due to TEAE (subdural hemorrhage). Combination therapy group showed a higher incidence of hematological TEAE (60.9% vs 39.1%) and infection (20.7% vs 7.7%). No TEAE-related death or new safety signals was recorded. Conclusion: This real-world analysis demonstrates that ibrutinib is effective and tolerable for R/R MCL in China. Ibrutinib-containing combination therapy outperformed ibrutinib monotherapy in response rate and TTR, but showed no survival benefits. The response rate data of ibrutinib monotherapy obtained from our study was different to existing clinical trial data, which may be mainly due to the short follow-up time of our study. Further analysis with longer follow-up is needed to validate these findings. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 3
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4444-4444
    Abstract: Purpose: Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is a rare and highly aggressive disease. The Ann Arbor staging system had been unsuitable to proper staging of ENKTL. This study was conducted to establish a new staging system specified for ENKTL, which can identify poor prognostic patients. Patients and Methods: Patients with untreated, centrally reviewed diagnosis of ENKTL were included in our study. The new staging system was established based on the study of single center consecutive patients treated with CHOP-like regimens with or without involved field radiotherapy (IFRT), then we initinated a multicenter confirmation study and conducted a multicenter prospective study to validate the new staging system. Results: From Jan 1997 to June 2006, 134 consecutive patients treated in the cancer center of Sun Yat-sen University were analyzed. The following was a summary of the classification system developed: stage I: lesions confined within nasal cavity or nasopharynx without local invasiveness (paranasal sinuses or bony or skin invasion); stage II: localized disease with local invasiveness; stage III: localized disease with regional lymph node involvement (cervical lymph nodes); and stage IV: disseminated disease (lymph nodes on both sides of diaphragm, multiple extranodal site). The distribution of stage I to IV using the new system and Ann Arbor system were 39.6%, 23.9%, 23.1%, 13.4% and 63.4%, 23.1%, 5.2%, 8.2%, respectively. The 5-year OS rate of stage I to IV using the new system were 29.5%, 23.4%, 21.3% and 0.07% compared with 23.8%, 21.3%, 0.0% and 0.0% using the Ann Arbor system. In the multicenter confirmation study conducted in 18 centers in China, 722 patients were analyzed. The results showed that the distribution of the new system compared with Ann Arbor system from stage I to IV were 24.1%, 34.9%, 18.3%, 22.7% vs 59.1%, 19.0%, 6.9%, 15.0%, respectively, and the 5-year OS rate of stage I to IV were 56.0%, 48.3%, 33.8%, 26.1% vs 50.7%, 39.1%, 10.8%, 28.0%, respectively. For the multicenter prospective study, 233 newly diagnosed ENKTL patients treated with non-CHOP-like regimens were enrolled and showed a balanced distribution of 17.2%, 39.9%, 19.3%, 23.6% vs 53.6%, 25.3%, 6.9%, 14.2% from stage I to IV and superior 5-year OS rate: 82%, 73%, 67%, 54% vs 75.2%, 65.6%, 46.9%, 73.8% from stage I to IV using the new system in compared with the Ann Arbor system. Conclusions: The new staging system with a more balanced distribution and a superior prognostic discrimination as compared with Ann Arbor staging system no matter for CHOP-like or non-CHOP-like regimens, is more suitable for ENKTL and can be recommended used in the future. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 8552-8552
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 7552-7552
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 7560-7560
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e13518-e13518
    Abstract: e13518 Background: The use of rituximab(RTX)for the treatment of primary central nervous system lymphoma(PCNSL) is controversial, and whether the RTX permeability of the blood-brain barrier can be improved by craniotomy is unknown. Methods: ImmunocompetentPCNSL patients newly diagnosed via craniotomy or stereotactic biopsy were enrolled and received RTX (375 mg/m 2 , Q3w) treatment. Systemicnon-Hodgkin's B cell lymphoma (systemic-B-NHL)patients without CNS involvement served as the control group. The trough concentrations of RTX (C RTX ) and CD19 levels in cerebrospinal fluid (CSF) and plasma were analyzed by ELISA and flow cytometry methods during each treatment cycle.The efficacy and adverse effects were recorded. Results: From December 2016 to February 2018, 21 PCNSL and 32 systemic-B-NHL patientswere enrolled. The CSF C RTX in the craniotomy-PCNSL group (0.2198±0.1866μg/ml) was significantly higher than those in the stereotactic-PCNSLgroup (0.0613±0.0408 μg/ml, P = 0.031) and the systemic-B-NHLgroup (0.0799±0.0614μg/ml, P = 0.046). The BBB penetrabilityof RTX in the craniotomy-PCNSL group (1.52±1.05%) was nearly four times that in the stereotactic-PCNSL group (0.41±0.19%, P = 0.048) and nearly three timesthat in the systemic-B-NHL group (0.54±0.61%, P = 0.012). No significant differences in the C RTX or BBB penetrability of RTX were observedbetween the stereotactic-PCNSL and systemic-B-NHL groups. CD19 levels in plasma fell below 0.1% in all patients before the second cycle of chemotherapy, and the time required for CSF CD19cell clearance in craniotomy-PCNSL patients tended to be reduced compared with that required by stereotactic-PCNSL patients. The CR and ORR rates of craniotomy-PCNSL patientswere 30% higher than those of stereotactic-PCNSL patients. Conclusions: The BBB penetrability of RTXand the CSF C RTX are significantly improved in PCNSL patients diagnosed via craniotomy.Rituximab could be recommended for routine use in craniotomy PCNSL patients. Clinical trial information: ChiCTR-TRC-11001687.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 8
    In: The Journal of Pathology, Wiley, Vol. 253, No. 2 ( 2021-02), p. 148-159
    Abstract: SETDB1 is a histone lysine methyltransferase that has critical roles in cancers. However, its potential role in gastric cancer (GC) remains obscure. Here, we mainly investigate the clinical significance and the possible role of SETDB1 in GC. We find that SETDB1 expression is upregulated in GC tissues and its high‐level expression was a predictor of poor prognosis in patients. Overexpression of SETDB1 promoted cell proliferation and metastasis, while SETDB1 suppression had an opposite effect both in vitro and in vivo . Mechanistically, SETDB1 was shown to interact with ERG to promote the transcription of cyclin D1 ( CCND1 ) and matrix metalloproteinase 9 ( MMP9 ) through binding to their promoter regions. In addition, the expression of SETDB1 was also enhanced by the transcription factor TCF4 at the transcriptional level in GC. Furthermore, SETDB1 expression was found to be induced by Helicobacter pylori ( H. pylori ) infection in a TCF4‐dependent manner. Taken together, our results indicate that SETDB1 is aberrantly overexpressed in GC and plays key roles in gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9. Our work also suggests that SETDB1 could be a potential oncogenic factor and a therapeutic target for GC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 1475280-3
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  • 9
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 14-16
    Abstract: Background: T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin's lymphoma with poor prognosis and lacks of standard treatment approaches. PAK2, a member of the p21 activated kinase (PAKs) family, is a component of the gene-expression-based classifier which made great contributions to prognostic prediction of T-LBL(Cai et al. Leukemia 2020). This study aims to analyze the expression of PAKs in human T-LBL cell lines and tissues to clarify its clinical significance and evaluate the therapeutic activity of PAKs inhibitor in T-LBL. Methods: The mRNA and protein expression levels of PAKs in human T-lymphoid cell lines (H9) and T-LBL cell lines (Jurkat, SUP-T1 and CCRF-CEM) were detected by quantitative real-time PCR and western blot, respectively. We retrospectively collected 69 Formalin-fixed, Paraffin-embedded (FFPE) samples and corresponding clinical information from T -LBL patients between September 2000 and May 2015 at Sun Yat-sen University Cancer Center (SYSUCC). Affymetrix Human Gene 2.0 ST microarray (Thermo Fisher Scientific, Waltham, MA, USA) was used to detect the expression of PAKs. Mann-Whitney U test was used for comparing the expression differences between relapsed and non-relapsed patients. Cumulative relapse-free survival (RFS) time was calculated using the Kaplan-Meier method (Expression level higher than the upper quartile (P75) was defined as PAK1 or PAK 2 high expression. High expression (median as cutoff point) of both PAK1 and PAK2 was defined as PAK1/2 high expression). Pearson's chi-square test and Fisher's exact test were used to compare the distribution of clinical variables. Correlations between PAK1, PAK2 and NOTCH1 were evaluated using Spearman's correlation coefficient. Two PAK inhibitors, PF3758309 (PF) and FRAX597, were used to block PAK kinase activity pharmacologically. Cell viability was determined using the viability assay kit CCK-8. Cell cycle and cell apoptosis were analyzed by flow cytometry. All statistical analyses were performed using SPSS 24.0 software (SPSS, Armonk, NY, USA) or GraphPad Prism 8.0 (GraphPad, La Jolla, CA, USA). A P value & lt; 0.05 was considered significant. The study protocol was approved by the Institutional Review Board of SYSUCC. Results: The mRNA and protein expression levels of PAK1 in T-LBL cell lines of Jurkat, SUP-T1 and CCRF-CEM cell lines were significantly higher than those in T-lymphoid cell lines H9 cell line (P & lt;0.05) (Figure 1). Of the 69 T-LBL patients, 44 (63.8%) were male and the median age at diagnosis was 30 years (range: 16-44). The majority (72.5%) of the patients received acute lymphoblastic leukemia (ALL)-type chemotherapy regimens. The PAK2 mRNA expression level of 32 patients with relapsed disease was significantly higher than that of 37 cases without relapse (P=0.012), and no difference was found in mRNA expression of PAK1, 3, 4, 7(Figure 2). Patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression (PAK1 mRFS 31.5 months vs not reached(NR), HR=3.001, P=0.028; PAK2 mRFS 25.7 months vs NR, HR=3.981, P=0.027)(Figure 3). Patients with high PAK1/2 mRNA expression experienced earlier relapse than patients with low PAK1/2 mRNA expression (mRFS 26.0 months vs NR, HR=2.721, P=0.032)(Figure 3). PAK1/2 mRNA expression was found to be associated with hemoglobin concentration, Ki-67 expression, pleural and pericardia effusion, bone marrow involvement and chemotherapy response (P & lt;0.05)(Table 1). Further, the PAK1 mRNA was correlated with the expression of NOTCH1, which is frequently mutated in T-LBL (r=0.5716, P & lt;0.0001)(Figure 4). The PAK inhibitors PF and FRAX597 demonstrated strong anti-tumor activity in vitro (Table 2). Both inhibitors suppressed cell proliferation in a time- and dose-dependent manner (Figure 5). Both inhibitors induced cell cycle arrest in the G1/0 phase, accompanied by corresponding S phase reductions in all tested cells(Figure 6). The synergistic effect between PAK inhibitor PF and doxorubicin was also observed (Figure 7). Besides, PF could inhibit the phosphorylation of PAK1/2, Cyclin D1 and NF-κB in Jurkat cell line(Figure 8). Conclusions: PAK1 and PAK2 play certain roles in the occurrence and recurrence of T-LBL, and their potential as novel biomarkers deserves further exploring. Our results underscore the potential of PAK inhibitor as effective target therapy for T-LBL. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 8508-8508
    Abstract: 8508 Background: Extranodal NK/T cell lymphoma, nasal type (ENKL) is more prevalent in Asia and has worse prognosis than B-NHL. No therapeutic strategy is currently identified for ENKL. This phase II/III study was undertaken to compare CHOP-B/IMVD/DHAP-Alternating Triple Therapy (CID-ATT) and standard CHOP regimen as first-line treatment prospectively. Methods:109 patients (pts) initially diagnosed as ENKL (16-70 ys old) with Ann Abor Stage I to II were randomized to receive CID-ATT or CHOP regimen from Jan 2006 to Jan 2012. CID-ATT alternated among CHOP-B, IMVD, and DHAP, given in alternating sequence for a total of 6 courses (2 circle). Involved field radiation was administered after 6 courses(2 circle) of CID-ATT regimen or 6 cycles of CHOP regimen. All pts received prophylactic granulocyte colony-stimulating factor, interleukin-11and thrombopoietin for each DHAP cycle. Results: 109 pts were evaluable (54CID-ATT; 55 CHOP). With a median follow-up of 40.3months,OS and PFS was significantly prolonged with CID-ATT compared with CHOP (1yOS :80.2% vs 78.6%, 3yOS:68.0% vs 42.3%, 5yOS: 64.2% vs 34.5%,P=0.023; 1yPFS: 74.9% vs 59.6%, 3yPFS:60.5% vs 32.0%, 5yPFS: 60.5% vs 32.0% ; P=0.016). Compared to CHOP group, CID-ATT group has a much higher complete remission rate (CID-ATT:47/54,87.0 % vs CHOP:29/55,52.7%, P 〈 0.001). The survivals for pts who achieved CR after One circle (3 courses) were significantly better than those who were in non-CR group.(5yOS: CR group in ATT:75.3%, non-CR group in ATT:51.5%, CR group in CHOP:39.3%, non-CR group in CHOP:31.0%; P=0.003). No treatment related death was observed, although Grade III/IV neutropenia (30/54,55.6%) and thrombocytopenia (33/54,61.1%) were observed in CID-ATT regimen, especially in DHAP cycle. Conclusions: Our study has demonstrated that the CID-ATT regimen as an optimal first-line therapy achieved promising clinical activity with safe and tolerated toxicity under close monitoring and good supportive care of untreated early staging ENKL pts. CR of induce chemotherapy following radiotherapy is very important for ENKL survival. Clinical trial information: CSWOG0002.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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